An aqueous extract of normal skin has been shown to contain an inhibitor of certain cell mediated immune reactions, mitogen-induced blastogenesis and cytotoxicity. Current studies investigated the effect of the inhibitor on cell membrane markers and antibody dependent cellular cytotoxicity. Significant diminution of E rosette formation was demonstrated using as little as 0.6 micrograms of the skin fraction (P less than .02). Fc receptors for both IgG and IgM were reduced by 46-96% of controls in the presence of the skin inhibitor. On the other hand, no effect on the detection of the complement receptor or surface immunoglobulin was observed, indicating some specificity of binding. In addition, the antibody dependent cell-mediated cytotoxic reaction was inhibited by the skin extract. It was shown that the inhibitor interacted with the lymphocytes, not the antibody or target cells. No effect was detectable when the skin fraction was added after the interactions of effector cells, antibody and target cells had occurred. This was in contrast to phytohemagglutinin induced cytotoxicity which could be inhibited following the preincubation of the lymphocytes with the mitogen. Thus there appears to be two mechanisms by which the skin fraction interferes with cellular responses: inhibition of antibody binding to Fc receptors, and interference with a step in cellular activation following mitogen stimulation. Analysis of the extract showed the inhibitor was inactivated by trypsin, and did not contain sialic acid, 5' nucleotidase or beta-N-acetylglucosaminidase, and thus was not associated with membrane or lysosomal enzymes.